Cross reactive TCR modulate the antiviral efficacy of protective HLA class I alleles (67.17)

Abstract

Abstract HLA class I alleles B27 and B57 are associated with protection against HIV-1 disease progression. However, the majority of persons expressing these alleles experience progressive infection, and factors modulating the HLA protective effect remain unclear. Here, we performed a detailed analysis of HIV-1-specific CD8 T cell responses in both progressors and controllers expressing HLA B27 or B57 in terms of TCR recruitment, polyfunctionality, proliferation, avidity, differentiation phenotypes, and functional ability to inhibit viral replication. The data show that HLA B27- or B57-restricted CD8 T cells targeting the same epitopes could be clearly differentiated between controllers and progressors based on potency and cross-reactivity of recognition of HIV-1 and viral variants. This in turn was associated with distinct TCR usage. Superior control of replication of HIV-1 and viral variants was observed by cross-reactive TCR-equipped CD8 T cells while highly antiviral efficacy was associated with polyfunctional CD8 T cells. These data indicate that the efficacy of protective alleles is associated with their ability to cross recognize viral variants, and this in turn is related to specific TCR clonotypes that are generated in natural infection. Clonally diverse CD8 T cell responses to a viral epitope increase the likelihood that multiple divergent strains of viruses may be recognized by cross-reactive CD8 T cells, and have potentially important implications for immunogen design.